Rh-DuPHOS-catalyzed enantioselective hydrogenation of enol esters. Application to the synthesis of highly enantioenriched α-hydroxy esters and 1,2-diols

Article abstract of DOI:10.1021/ja974278b

The asymmetric hydrogenation of α-(acetyloxy)- and α- (benzoyloxy)acrylates 4 catalyzed by cationic rhodium-DuPHOS complexes has been examined. A wide range of substrates (4) were prepared via a convenient Horner-Emmons condensation protocol, and subsequently hydrogenated under mild conditions (60 psi of H₂) at substrate-to-catalyst ratios (S/C) of 500. Overall, enol ester substrates 4 were reduced by the cationic Et-DuPHOS-Rh catalysts with very high levels of enantioselectivity (93-99% ee). Importantly, substrates 4 bearing β-substituents could be employed as E/Z isomeric mixtures with no detrimental effect on the selectivity. Labeling studies indicated that no significant E/Z isomerization of the substrates occurs during the course of these reactions. Details concerning optimization of the reaction, interesting solvent effects, and deprotection procedures for the synthesis of highly enantioenriched α-hydroxy esters and 1,2-diols also are provided.

Full text of DOI:10.1021/ja974278b

J. Am. Chem. Soc. 1998, 120, 4345-4353
4345
Rh-DuPHOS-Catalyzed Enantioselective Hydrogenation of Enol
Esters. Application to the Synthesis of Highly Enantioenriched
R-Hydroxy Esters and 1,2-Diols
Mark J. Burk,*,† Christopher S. Kalberg, and Antonio Pizzano‡
Contribution from the P. M. Gross Chemical Laboratory, Department of Chemistry, Duke UniVersity,
Durham, North Carolina 27706
ReceiVed December 17, 1997
Abstract: The asymmetric hydrogenation of R-(acetyloxy)- and R-(benzoyloxy)acrylates 4 catalyzed by cationic
rhodium-DuPHOS complexes has been examined. A wide range of substrates (4) were prepared via a
convenient Horner-Emmons condensation protocol, and subsequently hydrogenated under mild conditions
(60 psi of H2) at substrate-to-catalyst ratios (S/C) of 500. Overall, enol ester substrates 4 were reduced by the
cationic Et-DuPHOS-Rh catalysts with very high levels of enantioselectivity (93-99% ee). Importantly,
substrates 4 bearing â-substituents could be employed as E/Z isomeric mixtures with no detrimental effect on
the selectivity. Labeling studies indicated that no significant E/Z isomerization of the substrates occurs during
the course of these reactions. Details concerning optimization of the reaction, interesting solvent effects, and
deprotection procedures for the synthesis of highly enantioenriched R-hydroxy esters and 1,2-diols also are
provided.
Introduction
We envisioned that enantioselective hydrogenation of the
olefinic bond of enol esters may provide an alternative procedure
for the asymmetric catalytic synthesis of R-hydroxy esters (eq
1). Hence, we have set out to establish the feasibility of this
approach.
Numerous inherent practical advantages are associated with
asymmetric catalytic processes that allow the conversion of
prochiral substrates into valuable optically active products.1
Homogeneous enantioselective hydrogenation constitutes one
of the most versatile and efficacious of these methods, and the
development of improved catalysts for reduction of a broad
range of unsaturated substrates continues to evolve at a rapid
pace. Currently, asymmetric hydrogenation catalysts can
provide access to a wide variety of chiral compounds with
outstanding levels of efficiency and enantioselectivity through
reduction of the CdC, CdN, and CdO bonds.2 Prochiral
ketones represent a particularly important and challenging class
of substrates. A broadly effective and highly enantioselective
method for asymmetric hydrogenation of ketones could allow
the production of a plethora of extremely useful chiral alcohols,
which are ubiquitous in nature and are in great demand for the
design of pharmaceutical and agrochemical agents. Despite
various breakthroughs recently reported for the enantioselective
reduction of specific types of ketones,2,3 no general and efficient
catalytic system has yet been developed which provides
consistently high enantioselectivities for the hydrogenation of
R-keto esters to R-hydroxy esters.4 The latter compounds
comprise versatile building blocks in organic synthesis with
application, for instance, in the preparation of optically active
R-amino acids.5
Structurally, both R-(acyloxy)acrylates of type A and R-(acyl-
amino)acrylates of type B possess a carbonyl oxygen atom that
is situated three atoms from the olefin to be reduced and which
is properly aligned to facilitate chelation to a metal center (Fig-
ure 1). The topological similitude between A and B, combined
with the great level of success achieved in asymmetric hydrogen-
ation of substrates B, intimates the viability of enantioselective
reduction of R-(acyloxy)acrylates. Contrary to this expectation,
(3) See, for example: (a) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo,
N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J.
Am. Chem. Soc. 1988, 110, 629. (b) Takahashi, H.; Sakuraba, S.; Takeda,
H.; Achiwa, K. J. Am. Chem. Soc. 1990, 112, 5876. (c) Zhang, X.; Taketomi,
T.; Yoshizumi, T.; Kumobayashi, H.; Akutagawa, S.; Mashima, K.; Takaya,
H. J. Am. Chem. Soc. 1993, 115, 3318. (d) Ohkuma, T.; Ooka, H.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2675.
(e) Burk, M. J.; Harper, G. H.; Kalberg, C. S. J. Am. Chem. Soc. 1995,
117, 4423. (f) Roucoux, A.; Thieffry, L.; Carpentier, J.-F.; Devocelle, M.;
Meliet, C.; Agbossou, F.; Mortreux, A. Organometallics 1996, 15, 2440.
(4) (a) Spindler, F.; Pittelkow, U.; Blaser, H.-U. Chirality 1991, 3, 370.
(b) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.;
Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya,
H. J. Org. Chem. 1994, 59, 3064.
† Present address: Chirotech Technology Ltd., Chiroscience plc, Cam-
bridge Science Park, Milton Rd., Cambridge CB4 4WE, England.
‡ Present address: Instituto de Investigaciones Quimicas, 41092 Sevilla,
Spain.
(1) (a) Collins, A. N., Sheldrake, G. N., Crosby, J., Eds. Chirality in
Industry; John Wiley and Sons: New York, 1992. (b) Cornils, B., Herrmann,
W., Eds. Applied Homogeneous Catalysis with Organometallic Compounds;
VCH: Weinheim, 1996.
(2) (a) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH Publishers:
Weinheim, 1993. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley and Sons: New York, 1994.
(5) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergamon Press: Oxford, 1989.
S0002-7863(97)04278-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/28/1998

4346 J. Am. Chem. Soc., Vol. 120, No. 18, 1998
Burk et al.
Scheme 1. Synthesis of Horner-Emmons Reagent 3
Figure 1.
surprisingly little success has been disclosed regarding the design
of a generally effective catalyst for this useful transformation.6a,7
We recently have developed a series of efficient and highly
enantioselective Rh- and Ru-based hydrogenation catalysts
bearing 1,2-bis(2,5-dialkylphospholano)benzene (DuPHOS) and
1,2-bis(2,5-dialkylphospholano)ethane (BPE) ligands.3e,6 Sev-
eral years ago we reported preliminary findings regarding the
efficacy of these catalysts for the asymmetric hydrogenation of
various enol acetates.6a In particular, we demonstrated that the
Et-DuPHOS-Rh catalyst smoothly reduced methyl 2-acetoxy-
acrylate (A, R ) H) to the corresponding lactate derivative with
exceptional levels of absolute stereocontrol (>99% ee). More
recently, Schmid and co-workers at Hoffmann La Roche further
demonstrated the industrial utility of the Et-DuPHOS-Rh
catalyst for asymmetric hydrogenation of a specific enol
acetate.6g Finally, Schmidt et al.7a have reported the hydrogena-
tion of E/Z isomeric mixtures of several â-substituted R-(acyl-
oxy)acrylates with Rh-DIPAMP8a or Ru-BINAP8b catalysts.
However, neither of the latter catalysts displayed broad ap-
plicability in these reactions.
Herein we report successful application of our cationic
DuPHOS-Rh catalysts in the highly enantioselective hydro-
genation of a diverse array of R-acetoxy and R-benzoyloxy enol
esters (4). On the basis of our auspicious preliminary results,
we have endeavored to expand our studies to encompass a wide
range of â-substituted R-(acyloxy)acrylates. Details concerning
optimization of these reactions and the scope of the process are
provided herein. These studies culminate in the development
of a general and convenient process for the asymmetric catalytic
synthesis of R-hydroxy esters and 1,2-diols.
analogous to that used for the synthesis of R-enamide esters
(i.e., see B above). Despite the utility of 3 in the preparation
of substrates 4, the reported synthesis and purification of this
reagent was tedious and low yielding in our hands. Thus, during
the course of our investigations we have devised an improved
preparation of Horner-Emmons reagents 3, as generally
depicted in Scheme 1.
In a simple one-pot reaction, glyoxylic acid was condensed
with diethyl phosphite to provide in quantitative yield (by NMR)
the phosphonate acid 1. The phosphonate acid 1 is a versatile
intermediate that allows introduction of a wide range of different
acyl or carbamoyl protecting groups. For instance, reaction with
acetyl chloride or benzoyl chloride directly afforded the cor-
responding acetate or benzoate derivatives, 2-OAc or 2-OBz,
respectively, in good yield. Importantly, the acids 2 were easily
isolated and purified by recrystallization from methylene
chloride. Facile esterification with, for example, diazomethane
subsequently yielded the desired phosphonate methyl esters 3
in good overall yield for the three steps (60-70%).
With the Horner-Emmons reagent 3 in hand, the ultimate
hydrogenation substrates 4 were prepared readily through
tetramethylguanidine-mediated condensation with the appropri-
ate aldehyde, as previously described.7a The enol acetates and
benzoates (4) were thus obtained in good yield, and invariably
were isolated as E/Z isomeric mixtures (2:1 to 10:1). The E
isomer predominated for all substrates examined. Physical sepa-
ration of the geometric isomers of 4 proved difficult. Isomeriza-
tion of E/Z enol acetate mixtures to the pure Z isomer previously
has been reported in several instances,7a although this requires
additional synthetic steps and the results are rather capricious.
In light of this, development of a catalyst system which could
hydrogenate E/Z isomeric mixtures of substrates 4 with high
enantioselectivities would provide a new general method of great
synthetic utility. We next explored this possibility.
Results and Discussion
1. Preparation of Enol Ester Substrates (4). Synthesis
of the parent unsubstituted enol ester substrate, methyl 2-acet-
oxyacrylate (4a-OAc) proceeds readily through reaction be-
tween methyl pyruvate and acetic anhydride.6a However,
attempted extension of this procedure to â-substituted R-(acy-
loxy)acrylate derivatives proved relatively ineffectual.
A
convenient route to a potentially broad range of enol esters has
been reported and involves condensation of aldehydes with a
Horner-Emmons reagent such as 3.7a This procedure is
2. Hydrogenation Reactions: Optimization. We previ-
ously have demonstrated that cationic Rh catalysts bearing the
DuPHOS ligands are capable of hydrogenating a range of
olefinic substrates with exceedingly high enantioselectivities.6
However, it remains impossible to predict a priori which catalyst
will provide high enantioselectivities for a given substrate.
Results obtained with one substrate type generally cannot be
extended to other substrate types. This circumstance highlights
the importance of a modular ligand design which provides facile
access to a homologous series of ligands that may be examined
systematically in a given transformation. As expounded below,
we have explored the efficacy of a series of DuPHOS-Rh
catalysts in the asymmetric hydrogenation of enol ester sub-
strates of type 4. The present study was actuated in an effort
to develop a feasible asymmetric catalytic process for the
production of highly enantiomerically enriched R-hydroxy esters
and 1,2-diols.
(6) (a) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518. (b) Burk, M. J.;
Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115,
10125. (c) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc.
1995, 117, 7, 9375. (d) Burk, M. J.; Feng, S.; Gross, M. F.; Tumas, W. J.
Am. Chem. Soc. 1995, 117, 8277. (e) Burk, M. J.; Gross, M. F.; Harper, T.
G. P.; Kalberg, C. S.; Lee, J. R.; Martinez, J. P. Pure Appl. Chem. 1996,
68, 37. (f) Burk, M. J.; Allen, J. G.; Keisman, W. F. J. Am. Chem. Soc.
1998, 120, 657. (g) Crameri, Y.; Schmid, R.; Siegfried, T. European Patent
No. EP 0691325 A1, 1996.
(7) (a) Schmidt, U.; Langner, J.; Kirchbaum, B.; Braun, C. Synthesis
1994, 1138. (b) Koenig, K. E.; Bachman, G. L.; Vineyard, B. D. J. Org.
Chem. 1980, 45, 5, 2362. (c) Selke, R.; Pracejus, H J. Mol. Catal. 1986,
37, 213. (d) Brown, J. M.; Murrer, B. A. J. Chem. Soc., Perkin Trans. 2
1982, 489. (e) Fryzuk, M. D.; Bosnich, B. J. Am. Chem. Soc. 1978, 100,
5491.
(8) (a) DIPAMP ) 1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane;
see: Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.;
Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946. (b) BINAP ) 2,2-
bis(diphenylphosphino)-1,1′-binaphthyl; see: Noyori, R.; Takaya, H. Acc.
Chem. Res. 1990, 23, 345.
2.1. E/Z Isomeric Enol Benzoates 4-OBz. Our propitious
preliminary data involving enantioselective enol ester hydro-

EnantioselectiVe Hydrogenation of Enol Esters
J. Am. Chem. Soc., Vol. 120, No. 18, 1998 4347
Table 1. Hydrogenation of 4b-OBz with DuPHOS-Rh
Table 2. Hydrogenation of 4b-OBz in Different Solventsa
Catalystsa
entry
R in the DuPHOS Ligand
conversionb
% eec
1
2
3
4
5
(S,S)-Me
(S,S)-Et
(R,R)-n-Pr
(R,R)-i-Pr
(S,S)-Cy
100
100
100
50
98.8 (S)
97.0 (S)
98.5 (R)
52.6 (S)
0
entry
solvent
MeOH
i-PrOH
CF3CH2OH
EtOAc
THF
conversionb
% eec
30
1
2
3
4
5
6
7
100
100
60
60
80
0
100
97.0
99.3
98.0
90.0
96.5
a Reactions were carried out at room temperature under an initial
H2 pressure of 60 psig and as 0.2 M solutions of substrate 4b-OBz in
methanol using the catalyst precursor [(COD)Rh(DuPHOS)]OTf (0.4
mol %) for 12 h. b Conversions were determined by H-NMR. c En-
1
antiomeric excesses were determined by chiral HPLC as described in
the Experimental Section.
C6H6
CH2Cl2
99.8
a Reactions were carried out at room temperature under an initial
H2 pressure of 60 psi and as 0.2 M solutions of substrate 4-OBz using
the catalyst precursor [(COD)Rh(S,S)-Et-DuPHOS]OTf (0.4 mol %)
genation was obtained exclusively using the parent unsubstituted
substrate 4a-OAc (R ) H).6a Examination of the synthesis
and hydrogenation of substrates 4 bearing â-substituents was
the primary focus of this campaign. As outlined above, the
preparation of substrates via Horner-Emmons reagent 3
uniformly afforded inseparable E/Z isomeric mixtures of enol
esters 4. A critical determinant in our quest was the ability of
our Rh-DuPHOS catalysts to hydrogenate both E and Z enol
ester isomers 4 with comparably high enantioselectivity. Hence,
we examined the hydrogenation of a standard substrate, ethyl
2-(benzoyloxy)crotonate, 4b-OBz, to address this issue and to
identify the most suitable catalyst.
1
for 12 h. b Conversions were determined by H-NMR. c Enantiomeric
excesses were determined by chiral HPLC as described in the
Experimental Section.
Blackmond and co-workers reported compelling data that
implicate effective hydrogen concentrations as a key factor
controlling enantioselectivities in asymmetric hydrogenations;
higher pressures simply furnish higher H2 concentrations.10
Consistent with our previous results using the cationic Du-
PHOS-Rh catalyst systems,6 we have observed only a nominal
influence of pressure upon ee’s in the hydrogenation of 4b-
OBz using Et-DuPHOS-Rh over the range 15-90 psi of H2.
We have yet to examine higher pressures in this reaction,
although only minor pressure effects have been seen at pressures
up to 1500 psi (100 atm) in the hydrogenation of numerous
other substrates using these catalysts.6,11
Like pressure, the solvent employed in asymmetric catalytic
reactions can have a dramatic and unpredictable influence on
enantioselectivities and rates.2 Enantioselectivities manifested
by the cationic Rh-DuPHOS hydrogenation catalysts generally
exhibit token solvent dependency, although this effect can be
governed by substrate type. For example, enantioselectivities
in the DuPHOS-Rh-catalyzed hydrogenation of R-(N-acylami-
no)acrylates or R-arylenamides6,11 show very little solvent effect,
while the selectivities achieved in N-acylhydrazone hydrogena-
tions are highly solvent dependent.12
In an effort to further optimize the present reaction conditions,
we have examined the influence of solvent on enantioselectivi-
ties and relative rates in the Et-DuPHOS-Rh-catalyzed
hydrogenation of our standard substrate 4b-OBz. As the results
in Table 2 indicate, commensurately high enantioselectivities
may be achieved in most solvents examined, although somewhat
diminished ee’s were observed in ethyl acetate. In contrast,
the relative reaction rates were significantly affected by solvent
type. Complete conversion was observed in methanol and
2-propanol over 12 h, while lower conversion (60%) occurred
in the more lipophilic and more acidic 1,1,1-trifluoroethanol.
Similarly, reduced conversions were seen in polar aprotic
solvents such as tetrahydrofuran and ethyl acetate (entries 4 and
5), both of which may be expected to coordinate to the metal
and inhibit catalysis. In accord with this trend, the noncoor-
dinating, aprotic solvent methylene chloride was found superior,
allowing the attainment of both high ee’s and high relative rates.
We have investigated the hydrogenation of 4b-OBz (3:1 E/Z
mixture) using a series of DuPHOS-Rh catalysts derived from
the precursor complexes [(COD)Rh(DuPHOS)]+OTf- (COD )
1,5-cyclooctadiene, OTf ) trifluoromethanesulfonate) under a
standard set of reaction conditons (MeOH, 20 °C, 60 psi of H2,
S/C ) 250). The results of these studies are listed in Table 1.
The data in Table 1 clearly indicate that very high levels of
asymmetric induction are achievable in this reaction and that
E/Z substrate mixtures may be used with little or no adverse
influence upon enantioselectivities. Moreover, these results
show that catalysts bearing DuPHOS ligands possessing linear
alkylphospholane substituents (entries 1-3) all effect complete
conversion and provide comparably high enantioselectivities.
However, branched phospholane substituents, i-Pr and Cy
(entries 4 and 5), led to severe reduction in both rate and
enantioselection, evidently due to a significant increase in the
steric hindrance around the metal.
2.2. Pressure and Solvent Effects. The pressure under
which asymmetric catalytic hydrogenations are performed can
have a substantial impact on both observed rates and the
selectivities achieved in these reactions.9 These observations
may be attributed to either the formation of different catalytically
competent species in solution or the operation of kinetically
distinct catalytic cycles, at different pressures. Recently,
(10) Sun, Y.; Landau, R. N.; Wang, J.; Lebland, C.; Blackmond, D. J.
Am. Chem. Soc. 1996, 118, 1348.
(9) (a) Halpern, J. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1985; Vol. 5, p 41. (b) Sawamura, M.;
Kuwano, R.; Ito, Y. J. Am. Chem. Soc. 1995, 117, 9602. (c) Ojima, I.;
Kogure, T.; Yoda, N. J. Org. Chem. 1980, 45, 4728.
(11) Burk, M. J.; Lee, J. F.; Wang, Y. M. J. Am. Chem. Soc. 1996, 118,
5142.
(12) Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron
1994, 50, 4399.

4348 J. Am. Chem. Soc., Vol. 120, No. 18, 1998
Burk et al.
Scheme 2. Formation and Reactions of Benzene Adduct 6
This result was particularly useful for the hydrogenation of
naphthyl derivative 4k-OBz, which proved to be practically
insoluble in the alcohols mentioned above (vide infra). Overall,
inhibition by coordinating solvents such as THF and EtOAc
suggests that enol esters 4 are rather poorly coordinating
substrates that do not compete well for metal coodination sites.
This notion is corroborated further below.
2.3. Benzene Inhibition. A surprising result was obtained
when we attempted to perform the reaction in benzene solvent;
no hydrogenation of 4b-OBz was observed (entry 6, Table 2).
This result was curious since we previously have found benzene
to be a suitable, and sometimes superior, solvent for DuPHOS-
Rh-catalyzed hydrogenations.6c To categorically rule out the
presence of any impurity that may be inhibiting the catalyst,
competive hydrogenation of a 2:1 mixture of 4b-OBz and the
readily reduced enamide, methyl R-(N-acetylamino)acrylate, was
performed in benzene with the Et-DuPHOS-Rh catalyst.
After a 24 h reaction period, the enol benzoate 4b-OBz was
recovered unreacted while the enamide was completely reduced
to the expected N-acetylalanine methyl ester.
solvents such as acetonitrile to a CD2Cl2 solution of 6 led to
immediate displacement of the benzene ligand, returning its
characteristic proton signal at δ 7.15 ppm.
Formation of the stable adduct 6 indicated that benzene can
serve as a suitable ligand for Rh in these systems. Furthermore,
these studies suggested that the inhibitory effect of benzene in
the present enol benzoate hydrogenations may be due to the
inability of substrates 4 to displace the coordinated benzene in
6 and thus form the substrate-Rh intermediate complex required
for hydrogenation to proceed. That other substrates such as
R-(N-acylamino)acrylates, R-arylenamides, and N-acylhydra-
zones are readily hydrogenated by the DuPHOS-Rh catalysts
in benzene implies that these types of substrates are more
strongly coordinating than 4, and thus are capable of displacing
coordinated benzene from Rh (Scheme 2).
Support for these deductions derived from in situ NMR
experiments. The addition of 1 equiv of enol benzoate 4b-
OBz to a CD2Cl2 solution of the benzene adduct 6 effected no
changes in the NMR spectra relative to free 4b-OBz and 6. In
contrast, the addition of 1 equiv of methyl R-(N-acetylamino)-
acrylate to 6 instantaneously liberated benzene (1H NMR δ 7.15
(s)), and produced the known intermediate enamide-Rh-
DuPHOS complex 7.14b The 31P{1H} spectrum of 7 revealed
two inequivalent phosphorus nuclei appearing as doublets of
doublets centered at δ 80.6 ppm and δ 89.8 ppm, respectively
In an effort to further explore this effect, a benzene solution
of the catalyst precursor [((S,S)-Et-DuPHOS)Rh(COD)]+OTf-
was hydrogenated in the absence of substrate. After 1 h under
1
60 psi of hydrogen, H NMR studies indicated that cycloocta-
diene was cleanly converted to cyclooctane and a new stable
Rh complex was formed (Scheme 2). This complex was
isolated as a pale yellow solid that displayed characteristic NMR
2
(1JRhP ) 159 and 153 Hz, respectively, JPP ) 34 Hz), as ex-
pected. These observations strongly denote that enol benzoates
4 are not hydrogenated in benzene due to the incapability of 4
to effectively compete with benzene as a ligand for Rh. Taking
into consideration the binding affinity of RhP2+, fragments for
arenes,13,15 competition in the coordination between an aromatic
ring and an olefinic bond is plausible, and possibly explains
1
data [i.e., singlet at δ 6.7 ppm in the H NMR spectrum for
coordinated benzene, and a doublet centered at δ 95.4 ppm (1JRhP
) 204 Hz) in the 31P{1H} spectrum]. These data allowed
tentative identification of the complex as the η6-benzene adduct
[(S,S)-Et-DuPHOS)Rh(η6-benzene)]+OTf- (6).13,14 Consistent
with this assignment, the addition of strongly coordinating
+
(14) For other solvate complexes of the fragment RhP2 prepared by
(13) For other [(η6-C6H6)RhP2]+ complexes see: (a) Singewald, E. T.;
Slone, C. S.; Stern, C. L.; Mirkin, C. A.; Yap, G. P. A.; Liable-Sands, L.
M.; Rheingold, A. L. J. Am. Chem. Soc. 1997, 119, 3048. (b) Singewald,
E. T.; Shi, X.; Mirkin, C. A.; Schofer, S. J.; Stern, C. L. Organometallics
1996, 15, 5, 3062. (c) Bleeke, J. R.; Donaldson, A. J. Organometallics 1988,
7, 1588. (d) Schrock, R. A.; Osborn, J. A. J. Am. Chem. Soc. 1971, 93,
3089.
hydrogenation, see for example: (a) Miyashita, A.; Takaya, H.; Souchi,
T.; Noyori, R. Tetrahedron 1984, 40, 1245. (b) Armstrong, S. K.; Brown,
J. M.; Burk, M. J. Tetrahedron Lett. 1993, 34, 879.
(15) (a) Chaloner, P. A.; Esteruelas, M. A.; Joo, F.; Oro, L. A.
Homogeneous Hydrogenation; Kluwer Academic Publishers: Dordrecht,
The Netherlands, 1994. (b) Halpern, J.; Riley, D. P.; Chan, A. S. C.; Pluth,
J. J. J. Am. Chem. Soc. 1977, 99, 8055.

EnantioselectiVe Hydrogenation of Enol Esters
J. Am. Chem. Soc., Vol. 120, No. 18, 1998 4349
Table 3. Et-DuPHOS-Rh-Catalyzed Asymmetric Hydrogenation
of Enol Esters 4a
E isomer predominates) is noteworthy. It is well-documented
that enantioselectivities dramatically diminish when E isomers
of aromatic R-enamides (e.g., R-N-acetamidocinnamic acid and
analogous substrates) are used in asymmetric hydrogenation
reactions.2,8a Pertinently, the phenyl substrate (E)-4i-OAc has
been reported to be unreactive toward hydrogenation by both
the Ru-BINAP and Rh-DIPAMP catalysts previously used
to hydrogenate enol acetates.7a The latter catalysts ostensibly
are substrate specific and are capable of hydrogenating â-aro-
matic substrates 4 only when prepared in isomerically pure form.
In contrast, the Et-DuPHOS-Rh catalyst is a versatile system
that may be employed to hydrogenate a broad range of E/Z-
isomeric enol acylates 4.
Interestingly, several aromatic substrates were found relatively
unreactive under the standard reaction conditions originally
employed. For example, substrate 4i-OAc reacted appreciably
more slowly than its counterpart benzoate 4i-OBz, showing
only 10% conversion after 2 days of reaction. Curiously, the
analogous o-, m-, and p-bromophenyl enol benzoates also
reacted sluggishly under similar conditions. In these instances,
the less sterically demanding Me-DuPHOS-Rh catalyst often
was found to allow hydrogenation with faster rates and with
comparably high enantioselectivities. Hence, (S,S)-Me-Du-
PHOS-catalyzed hydrogenation of 4i-OAc afforded the reduced
product (S)-5i in 95.6% ee over 48 h.
We previously have demonstrated that the Me-DuPHOS-
Rh and Me-BPE-Rh catalysts are capable of hydrogenating
â,â-disubstituted R-acetamidoacrylate substrates with very high
enantioselectivities.6c The ability of the Rh-DuPHOS catalysts
to hydrogenate E/Z-isomeric mixtures of the enol esters 4 sug-
gested that these catalysts might also tolerate substituents in
both E and Z â-positions of an enol ester substrate. Unfortu-
nately, neither the Et-DuPHOS-Rh nor the less encumbered
Me-DuPHOS-Rh catalysts proved to be effective for the
hydrogenation of ethyl 2-(benzoyloxy)-3-methylbutenoate (8).
Somewhat greater success was achieved through use of the
more electron-rich and sterically least demanding Me-BPE-
Rh catalyst. Under the optimum conditions recently employed
in our laboratory for the hydrogenation of â,â-disubstituted
R-enamides (90 psig of hydrogen, cationic (S,S)-Me-BPE-
Rh catalyst)6c the desired product 9 was obtained with reasonable
enantioselectivity (82% ee).
substrate
R′
R
R′′
E/Z ratio
% eeb (conf)c
4a-OAc
4b-OBz
4c-OBz
4d-OAc
4d-OBz
4e-OBz
4f-OBz
4g-OAc
4g-OBz
4h-OBz
4i-OAc
4i-OBz
4j-OBz
4k-OBz
Ac
Bz
Bz
Ac
Bz
Bz
Bz
Ac
Bz
Bz
Ac
Bz
Bz
Bz
H
Et
Et
Me
Et
Et
Me
Et
Et
Et
Me
Et
>99 (S)
96.0 (S)
98 (S)
Me
n-Pr
i-Pr
i-Pr
c-Pr
CH2-i-Pr
n-C5H11
n-C5H11
c-C6H11
Ph
3
3
6
6
9
2.5
3.5
3.5
3
9
10
3
96.1 (S)d
96.9 (S)d
97.5 (S)
>99 (S)
>99 (R)e
>99 (S)
95 (S)
95.6 (S)f
98 (S)
Ph
Me
Et
Me
R-naphthyl
2-thienyl
93.2 (S)g
97.5 (S)
4
a Reactions were carried out at room temperature under an initkal
H2 pressure of 60 psig and as 0.5 M solutions in methanol of substrate
using the catalyst precursor [(COD)Rh(S,S)-Et-DuPHOS]OTf (0.2 mol
%) for 48 h unless otherwise stated. b Enantiomeric excesses were
determined by chiral HPLC or chiral capillary GC, as described in the
Experimental Section. c Absolute configurations were assigned by
comparing the sign of optical rotation of derived R-hydroxy esters or
1,2-diols with that of known compounds. d Initial pressure 90 psig.
f
e Reaction catalyzed by (R,R)-Et-DuPHOS-Rh. Reaction performed
witht the (S,S)-Me-DuPHOS-Rh catalyst (0.4 mol %). g Reaction
performed in methylene chloride.
the low reactivity we have observed in attempted hydrogena-
tion of several aryl-containing enol benzoates of type 4 (vide
infra).
3. Hydrogenation Reactions: Scope and Limitations. Our
overall objective was to develop a practical route to a diverse
range of enantiomerically pure R-hydroxy esters and 1,2-diols
through development of a broadly effective catalyst for asym-
metric hydrogenation of enol acylates of type 4. On the basis
of our promising results outlined above, we next endeavored
to explore the scope and limitations of the Et-DuPHOS-Rh
catalyst. Our preliminary optimization studies indicated that
enol acylates 4 were reduced more slowly than R-enamide or
N-acylhydrazone substrates under analogous conditions. None-
theless, under a standard set of mild conditions (MeOH, 20 °C,
S/C ) 500, 60 psi of H2, 48 h), the catalyst precursor
[(COD)Rh(Et-DuPHOS)]+OTf- induced the highly enantiose-
lective hydrogenation of a wide array of enol acetates and enol
benzoates 4 (Table 3). In all cases, substrates 4 were employed
as mixtures of E and Z isomers.
Substrates lacking â-substituents (4a, R ) H) or bearing linear
or branched â-alkyl substituents (4b-d, 4f,g) were hydrogenated
with very high enantiomeric excesses ranging from 97% ee to
higher than 99% ee. Similarly high enantioselectivities also
were seen with â-cycloalkyl substituents; 5e and 5h were
produced in 95% ee and 97.5% ee, respectively.
Importantly and unexpectedly, the Et-DuPHOS catalysts also
were capable of providing high selectivites with substrates
containing various aromatic â-substituents. Thus, the esters 5i,j
were obtained with excellent levels of enantioselectivity (98%
ee, 95.6% ee, and 93.2% ee, respectively). Even the thiophene-
containing substrate 4k was tolerated by the catalyst and was
reduced with high enantioselectivity (97.5% ee).
4. Mechanistic Examination of E/Z Isomerization. Above
we have shown that the DuPHOS-Rh catalysts are capable of
hydrogenating E/Z mixtures of substrates 4 with high levels of
enantioselectivity. These results brought to light two ques-
tions: (i) Are the E and Z isomers reduced with comparable
enantioselectivities? (ii) If E and Z isomers are reduced with
different selectivites, is isomerization of one isomer to the other
occurring (i.e., E to Z), such that the reduction proceeds through
only one isomeric pathway?
To address these issues, we examined separately the Et-
DuPHOS-Rh-catalyzed deuteration of individual E and Z
isomers of naphthyl derivative 4j-OBz, which may be separated
by column chromatography.16 Assuming the expected occur-
rence of stereoselective metal-catalyzed cis addition of D2 to
The attainment of high enantioselectivities in the hydrogena-
tion of E/Z mixtures of aromatic substrates 4i-k (in which the

4350 J. Am. Chem. Soc., Vol. 120, No. 18, 1998
Burk et al.
Figure 2. Benzylic region in the 1H NMR (acetone-d6) spectra of the deuteration products derived from (a) (z)-4j-OBz, (b) a 1:1 E/Z mixture of
4j, and (c) (E)-4j-OBz.
the olefinic bond of the substrate 4j-OBz, deuteration of pure
E and Z isomers should afford diastereomerically distinct
products which may be distinguished by 1H NMR spectroscopy
(diastereotopic â-protons). Table 3 indicates that the (S,S)-Et-
DuPHOS-Rh catalyst affords products 5 with S absolute
stereochemistry at the 2-R-position. Hence, deuteration of the
(Z)-4j-OBz using (S,S)-Et-DuPHOS-Rh should furnish (2S,3S)-
5j-OBz, while deuteration of E-4j-OBz should yield the 2S,3R
product (Figure 2). Any degree of isomerization of either E or
Z isomer would create a discernible mixture of diastereomers.
In the event of complete isomerization of one isomer to the
other, both E and Z isomers of 4j-OBz would provide the same
diastereomer of product D2-5j-OBz.
known display such a combination of substrate structural
tolerance and high enantioselectivity in asymmetric hydrogena-
tion reactions.
5. r-Hydroxy Esters and 1,2-Diols. An important applica-
tion of the hydrogenation reactions described herein conceivably
will be the preparation of highly enantiomerically enriched
R-hydroxy esters or 1,2-diols directly from hydrogenation
products 5. An obvious requirement is that transformations
involving 5 proceed with no loss of enantiomeric purity.
The requisite R-hydroxy esters 10 can be obtained readily in
good isolated yield by treatment of the hydrogenation products
5 with a 1:1 mixture of MeOH (or EtOH)-concentrated HCl.
Deprotection of acetates 5-OAc proceeded smoothly at room
temperature and were complete within 12 h. In contrast,
hydrolysis of benzoates 5-OBz required somewhat more forcing
conditions: 12-24 h under reflux in 1:1 MeOH (or EtOH)-
concentrated HCl. In neither case was racemization observed.
Conveniently, conversion to R-hydroxy esters 10 may be
achieved simply through addition of an equal volume of
concentrated HCl to the MeOH solution of 5 formed in the
hydrogenation reactions.
1
Figure 2 shows the benzylic region of the H NMR spectra
corresponding to the products of such reactions. The center
spectrum (b) corresponds to the product derived from deuteration
of a 1:1 E/Z mixture of isomers with an achiral catalyst.17 As
can be seen, deuteration of (Z)-4j-OBz and (E)-4j-OBz
produced diastereomers that differ only in the configuration at
the â-carbon C3. Comparison of the spectra revealed that
negligible isomerization occurred during (S,S)-Et-DuPHOS-
Rh-catalyzed deuteration of either (Z)-4j-OBz or (E)-4j-OBz.
The high enantioselectivites we have acheived in the hydro-
genation of isomeric mixtures of enol esters 4 suggests that the
Et-DuPHOS-Rh catalysts preferentially induce the same sense
of chirality and relative degree of selectivity at the R-carbon
(C2) of 4, with general disregard for the geometric configuration
about the â-carbon of the olefinic substrate. In accord with
this observation, independent deuteration of isomerically pure
(Z)-4j-OBz and (E)-4j-OBz with the (S,S)-Et-DuPHOS
catalyst provided the products (2S,3S)-5j and (2S,3R)-5j in 96%
ee and 89% ee, repectively.
By way of example, the benzoyl protecting group of 5i-OBz
(R ) Ph) was hydrolytically removed under the above conditions
to afford the corresponding R-hydroxy ester 10i in 85% yield.
Enantiomeric excess determination by chiral HPLC confirmed
that no racemization had occurred during deprotection of 5i-
OBz. Analogous behavior was observed in the synthesis of
other R-hydroxy esters using these procedures.
These results clearly demonstrate the unique ability of the
DuPHOS-Rh catalysts to tolerate substituents, even bulky
aromatic substituents, in either the E or Z â-position of enol
ester substrates 4. Distinctly, few other catalysts presently
(16) Olefin configuration has been assigned on the basis of the value of
3
the coupling constant JCH in -HCdC(CO2Et)(OBz): Fischer, P.; Sch-
weizer, E.; Langner, J.; Schmidt, U. Magn. Reson. Chem. 1994, 567.
(17) Configurations of the deuterated products have been assigned
considering cis addition of D2 to the olefinic bond: (a) Thompson, H. W.;
McPherson, E. J. Am. Chem. Soc. 1974, 96, 6332. (b) Kirby, G. W.; Michael,
J. J. Chem. Soc., Perkin Trans. 2 1973, 115.
Rather than hydrolytic conversion to R-hydroxy esters,
valuable chiral 1,2-diols 11 may be obtained simply through
treatment of hydrogenation products 5 with reducing agents such

EnantioselectiVe Hydrogenation of Enol Esters
J. Am. Chem. Soc., Vol. 120, No. 18, 1998 4351
(FAB): m/z 317.0782 (MH+ exact mass calculated for C13H18O7P,
317.0790).
as lithium aluminum hydride. Again, no loss of enantiomeric
purity was observed in these reactions. This procedure provides
an extremely facile entry into a diverse range of important chiral
building blocks which are not easily obtained by other asym-
metric catalytic methods. For instance, Sharpless’s asymmetric
dihydroxylation reaction performs exceedingly well with internal
olefins, but affords significantly lower enantioselectivites with
terminal olefins,18 which would be required to produce 1,2-
diols of type 11.
6. Conclusions. We have described the development of an
extremely effective catalyst for the enantioselective hydrogena-
tion of enol esters of type 4. In particular, the cationic Et-
DuPHOS-Rh catalysts have been found to allow the hydro-
genation of E/Z-isomeric mixtures of 4 with enantioselectivites
generally >97% ee. Deuteration studies indicated that no sub-
strate isomerization occurs during these reactions. Benzene was
found to inhibit the reaction through formation of a stable adduct
between benzene and the cationic Et-DuPHOS-Rh fragment.
The hydrogenation products 5 were converted readily to valuable
R-hydroxy esters or 1,2-diols with no diminution of enantiomeric
purity. The simplicity and versatility of the process described
herein suggest many possible applications in the synthesis of a
diverse range of important chiral building blocks.
Methyl 2-(diethylphosphoryl)-2-(O-benzoyl)Ethanoate (3). The
acid 2 (2.7 g, 8.6 mmol) was reacted with diazomethane using standard
procedures19 to provide the methyl ester 3 as a colorless oil; yield 2.7
1
g, 8.2 mmol, 95%; H NMR (CDCl3) δ 1.29 (m, 6H, -OCH2CH3),
2
3.78 (s, 3H, -COOCH3), 4.23 (m, 4H, -OCH2CH3), 5.65 (d, JPH
)
16.8 Hz, 1H, -P(O)CH-), 7.40-8.05 (m, 5H, -OC(O)C6H5); 13C
3
2
NMR (CDCl3) δ 16.1 (d, J ) 5.8 Hz), 52.9, 64.0 (d, J ) 7.1
PC
PC
1
Hz), 68.5 (d, J
) 158.9 Hz), 128.2, 128.4, 129.8, 133.7, 164.9,
PC
165.4; HRMS (FAB) m/z 331.0952 (MH+ exact mass calculated for
C14H20O7P, 331.0947).
Synthesis of Enol Esters 4. Condensation Reactions: General
Procedure. The procedure employed was as described in ref 7a.
Phosphonate ester 3 (5 mmol) and LiCl (5.5 mmol) were dissolved in
THF (10 mL) and cooled to -78 °C. Tetramethylguanidine (5.5 mmol)
was added, and after 15 min of stirring at -78 °C, the appropriate
aldehyde (6 mmol) was added. The reaction was then allowed to stir
while being warmed to room temperature over a period of 12 h. Ethyl
acetate-water, 1:1 (15 mL) was added, the organic fraction washed
with 1 N H2SO4 (2 × 15 mL) and 1 M NaHCO3 (2 × 15 mL) and
dried over MgSO4, and the solvent removed on a rotary evaporator.
Column chromatography was then performed to give the desired
products 4a-m. Where relevant, all products obtained were identical
in all repects to those previously reported.7a
Asymmetric Hydrogenations: General Procedure. In a glovebox,
a Fisher-Porter tube was charged with substrate, deoxygenated MeOH,
and catalyst (0.2 mol % unless otherwise stated). After being removed
from the glovebox, the vessel was connected to a hydrogen line and
subjected to five vacuum/H2 cycles, and the tube was pressurized to
an initial pressure of 60 psig of H2. The reaction was allowed to stir
for 48 h at room temperature. Once the reaction was finished, the
solvent was removed via rotary evaporation. The oily residue was
dissolved in ethyl acetate-hexanes (1:1) and passed through a short
plug of silica to remove the catalyst. Without further purification the
enantiomeric excesses were determined with an aliquot of the crude
product thus obtained. Spectroscopic and other analytical data for the
hydrogenation products 5 are given below.
7. Experimental Section
General Procedures. All reactions and manipulations were per-
formed under nitrogen either in a Braun Labmaster 100 glovebox or
using standard Schlenk-type techniques. Benzene, diethyl ether (Et2O),
tetrahydrofuran (THF), hexanes, and pentane were distilled from
sodium-benzophenone ketyl under nitrogen. Methylene chloride (CH2-
Cl2) was distilled from CaH2 and methanol (MeOH) from Mg(OMe)2.
Chiral DuPHOS ligands and rhodium catalysts were prepared as
previously described.6 Hydrogen gas (99.99%) was purchased from
National Welders, Inc. (Raleigh, NC) and used as received. Column
chromatography was performed using EM Science Silica Gel 60 (230-
400 mesh). All reagents were purchased from commercial suppliers
and used as received.
GC analyses were performed by using a Hewlett-Packard Model
HP 5890 Series II gas chromatograph. HPLC analyses were performed
using a Hewlett-Packard Model HP 1090 Series II liquid chromatograph
interfaced to a HP Vectra 486/66U computer workstation. Optical
rotations were measured using a Perkin-Elmer 241 polarimeter. HRMS
data were obtained using a JEOL JMS-SX 102A mass spectrometer.
NMR spectra were obtained on a Varian XL-300 (299.9 MHz, 1H; 121.4
MHz, 31P; 75.4 MHz, 13C) or a GE QE-300 (300.0 MHz, 1H; 75.5 MHz,
13C) spectrometer with chemical shifts reported in ppm (δ) relative to
Me4Si or residual protons in the solvent.
(R)-2-(Benzoyloxy)butanoic Acid, Ethyl Ester [(R)-5b-OAc]: oil;
1
3
[R]25 ) -1.8° (c 0.44, CHCl3); H NMR (CDCl3) δ 1.10 (t, JHH
)
D
3
3
7.4 Hz, 3H), 1.29 (t, JHH 7.1 Hz), 2.04 (m, 2H), 4.24 (q, JHH ) 7.1
Hz, 2H), 5.18 (t, JHH ) 6.6 Hz, 1H), 7.47,7,59, 8.09 (m, 5H); 13C
3
NMR (CDCl3) δ 9.4, 13.9, 24.5, 61.0, 73.6, 128.2, 129.6, 133.0, 133.1,
165.9, 169.9; HRMS (EI, direct insert) m/z 236.1047 (M+, exact mass
calcd for C13H16O4, 236.1047); ee determination (HPLC, Daicel Chiracel
OJ, 0.5 mL/min,15% 2-PrOH-hexanes) (R) t1 ) 16.56 min, (S) t2 )
18.50 min.
(S)-2-(Benzoyloxy)pentanoic Acid, Methyl Ester [(S)-5c-OBz]:
1
3
oil; [R]25 ) -11.9° (c 0.27 MeOH); H NMR (CDCl3) δ 0.99 (t, J
HH
D
) 7.5 Hz 3H), 1.55 (m, 2H), 1.97 (m, 2H), 3.77 (s, 3H), 5.25 (dd,
3J HH ) 7.5, 5.1 Hz, 1H), 7.43-8.10 (m, 5H); 13C{1H} NMR (CDCl3)
δ 13.6, 18.5, 33.2, 52.2, 72.5, 128.3, 129.4, 129.8, 133.2, 166.0, 170.8;
HRMS (FAB): m/z 237.1125 (MH+ exact mass calculated for C13H17O4,
237.1127); ee determination (HPLC, Daicel Chiracel OJ, 0.5 mL/min,
2.5% 2-PrOH-hexanes) (R) t1 ) 20.65 min, (S) t2 ) 21.99 min.
(R)-2-Acetoxy-4-methylpentanoic Acid, Ethyl Ester [(R)-5d-
OAc]: oil; [R]25D ) +19.8° (c 0.59, CHCl3); 1H NMR (CDCl3) δ 0.93
(t, 3JHH ) 7.9 Hz, 3H), 0.95 (d, 3JHH ) 8.1 Hz, 3H), 1.27 (t, 3JHH ) 7.1
Hz), 1.62 (m, 1H), 1.74 (m, 1H), 2.13 (s, 3H), 4.20 (q, 3JHH ) 7.2 Hz,
2H), 5.00 (m, 1H); 13C{1H}NMR (CDCl3) δ 13.3, 19.8, 20.7, 22.2,
38.9, 60.4, 70.3, 169.7, 169.9; HRMS (EI, direct insert) m/z 203.1290
(MH+, exact mass calcd for C10H18O4, 203.1283); ee determination,
derivatized to 4-methyl-2-hydroxypentanoic acid, ethyl ester, vide infra.
(S)-2-(Benzoyloxy)-4-methylpentanoic Acid, Ethyl Ester [(S)-5d-
OBz]: oil; [R]25D ) -10.9° (c 0.44, CHCl3); 1H NMR (CDCl3) δ 0.98
Synthesis of Phosphonate Reagent 3. 2-(Diethylphosphoryl)-2-
(O-benzoyl) ethanoic Acid (2). Glyoxylic acid monohydrate (2.0 g,
21.7 mmol) and diethyl phosphite (3.0 g, 21.7 mmol) were heated with
stirring to 60 °C for 5 h, after which the conversion to 1 was shown to
1
be complete by H NMR spectroscopy. Dichloromethane (20 mL),
pyridine (1.71 g, 21.7 mmol), and benzoyl chloride (3.05 g, 21.7 mmol)
were added and the reaction was allowed to stir for another 6 h.
Pyridinium chloride that precipitated was filtered, and the resulting
solution was washed with 1 M HCl (2 × 20 mL) and saturated NaHCO3
(20 mL). After the organic layer was dried over MgSO4, the solvent
was evaporated using a rotary evaporator. The resulting oil was taken
up in a small amount of CH2Cl2 and cooled. Colorless crystals of the
benzoyl-protected phosphonate acid 2 were thus obtained: yield 5.5
1
g, 17.3 mmol, 80%; H NMR (CDCl3) δ 1.30 (m, 6H, -OCH2CH3),
4.28 (m, 4H, -OCH2CH3), 5.78 (d, 2JPH ) 17.7 Hz, 1H, -P(O)CH-),
3
3
3
7.40-8.10 (m, 5H, -OC(O)C6H5), 11.04 (br, 1H, -COOH); 13C NMR
(d, JHH ) 8.4 Hz, 3H), 1.00 (d, JHH ) 8.4 Hz, 3H), 1.27 (t, JHH
)
7.1 Hz, 3H), 1.79 (m, 1H), 1.90 (m, 1H), 4.22 (q, 3JHH ) 7.1 Hz, 2H),
3
2
(CDCl3) δ 16.2 (d, JPC ) 5.8 Hz), 64.7 (d, JPC ) 10.1 Hz), 68.3 (d,
1JPC ) 160.2 Hz), 127.5, 128.4, 130.0, 133.7, 164.8, 166.4; HRMS
3
1.79 (m, 1H), 1.90 (m, 1H), 4.22 (q, JHH ) 7.1 Hz, 2H), 5.25 (dd,
3JHH ) 9.7, 3.9 Hz, 1H), 7.45, 7.54, 8.09 (m, 5H); 13C{1H} NMR
(19) Black, T. H. Aldrichim. Acta 1983, 16, 3.
(18) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 4, 2483.

4352 J. Am. Chem. Soc., Vol. 120, No. 18, 1998
Burk et al.
(CDCl3) δ 13.3, 20.9, 22.3, 24.0, 39.1, 60.5, 70.8, 127.9, 129.0, 132.5,
139.8, 165.3, 169.8; HRMS (EI, direct insert) m/z 265.1445 (M+, exact
mass calcd for C15H20O4, 265.1440); ee determination, derivatized to
4-methyl-1,2-pentanediol, vide infra.
(S)-2-(Benzoyloxy)-3-cyclopropylpropanoic Acid, Methyl Ester
[(S)-5e-OBz]: oil; [R]25D ) -12.7° (c 0.25, CHCl3); 1H NMR (CDCl3)
δ 0.15 (m, 2H), 0.49 (m, 2H), 0.90 (m, 1H), 1.87 (m, 2H), 3.73 (s,
3H), 5.30 (dd, 3J HH ) 7.5, 4.5 Hz, 1H), 7.40-8.15 (m, 5H); 13C{1H}
NMR (CDCl3) δ 4.0, 4.7, 7.1, 36.3, 52.2, 73.1, 128.5, 129.4, 129.8,
133.3, 165.9, 170.6; HRMS (FAB) m/z 249.1129 (MH+, exact mass
calcd for C14H17O4, 249.1127); ee determination (HPLC, Daicel Chiracel
OJ, 0.5 mL/min, 7.5% 2-PrOH-hexanes) (S) t1 ) 21.05 min, (R) t2 )
23.39 min.
m/z 348.1368 (M+, exact mass calcd for C22H20O4, 348.1362); ee
determination, derivatized to 3-(â-naphthyl)-1,2-propanediol, vide infra.
(S)-2-(Benzoyloxy)-3-(2′-thienyl)propanoic Acid, Methyl Ester
1
[(S)-5k-OBz]. [R]20 ) -27.7° (c 0.53 MeOH); H NMR (CDCl3)
D
δ 3.54 (m, 2H), 3.76 (s, 3H), 5.50 (m, 1H), 6.96-8.12 (m, 8H); 13C-
{1H} NMR (CDCl3) δ 31.6, 52.3, 72.8, 124.7, 124.9, 126.7, 128.3,
129.0, 129.8, 133.3, 137.2, 165.6, 169.3; HRMS (FAB) m/z 291.0684
(MH+ exact mass calculated for C15H15O4S, 291.0691), ee determination
(HPLC, Daicel Chiracel-OJ, 10% 2-PrOH-hexanes, 0.5 mL/min) (R)
t1 ) 38.1 min, (S) t2 ) 41.2 min.
Synthesis of r-Hydroxy Esters 10 and 1,2-Diols 11 from R-Acyl-
oxy Esters 5. Products 10 and 11 were obtained as described in the
text above. All products were authenticated by comparative analysis
with the spectroscopic data available in the literature. Comparison of
the sign of optical rotation with that reported was used to determine
configuration, as well as to corroborate the expected configuration of
the hydrogenation products 5 (i.e. the S,S configuration in the DuPHOS
ligand affords S products 5).
Hydrolysis of Esters 5: General Procedure. The 2-acetoxy esters
5-OAc were treated at room temperature with a mixture of ethanol
(or methanol) and concentrated HCl (1:1 v/v). Complete hydrolysis
to 10 was observed after 12 h at room temperature for 5-OAc
derivatives. Following the same procedure, complete hydrolysis
required 24 h of heating under reflux for 5-OBz esters.
(S)-2-(Benzoyloxy)-5-methylhexanoic Acid, Ethyl Ester [(S)-5f-
1
OBz]: oil; [R]25 ) -5.8° (c 0.57, CHCl3); H NMR (CDCl3) δ 0.90
D
3
3
(d, JHH ) 6.6 Hz, 6H), 1.28 (t, JHH ) 7.1 Hz, 3H), 1.39 (m, 1H),
1.77 (m, 1H), 1.99 (m, 2H), 4.23 (q, 3JHH ) 7.0 Hz, 2H), 5.19 (t, 3JHH
) 6.3 Hz, 1H), 7.46, 7.59, 8.08 (m, 5H); 13C{1H} NMR (CDCl3) δ
13.8, 21.9, 22.2, 27.3, 28.8, 33.8, 59.8, 60.8, 128.0, 129.3, 129.4, 133.0,
165.6, 169.8; HRMS (EI, direct insert) m/z 279.1593 (M+, exact mass
calcd for C16H22O4, 279.1596); ee determination: derivatized to
5-methyl-1,2-hexanediol, vide infra.
(S)-2-Acetoxyoctanoic acid, Ethyl Ester [(S)-5g-OAc]: oil; [R]25
D
) -21.1° (c 0.44, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, 3JHH ) 6.5 Hz,
3
3H), 1.27 (m, 11 H), 2.14 (s, 3H), 4.20 (q, JHH ) 7.1 Hz, 2H), 4.96
(S)-2-Hydroxy-4-methylpentanoic Acid, Ethyl Ester:20 [R]20
)
D
3
(t, JHH ) 6.5 Hz, 1H); 13C{1H} NMR (CDCl3) δ 13.5, 13.6, 20.1,
1
3
-18.1R (c ) 1.2, Et2O); H NMR (CDCl3) δ 0.94 (d, JHH ) 6.7 Hz,
22.1, 24.6, 28.4, 30.7, 31.2, 60.6, 72.0, 169.8, 169.9; HRMS (EI, direct
insert) m/z 231.1600 (M+, exact mass calcd for C12H22O4, 231.1596);
ee determination, derivatized to (S)-1,2-octanediol, vide infra.
(R)-2-(Benzoyloxy)octanoic Acid, Ethyl Ester [(R)-5g-OBz]: oil;
3
3
3H), 0.95 (d, JHH ) 6.6 Hz, 3H), 1.29 (t, JHH ) 7.2 Hz, 3H), 1.54
3
(m, 2H), 1.89 (h, JHH ) 6.7 Hz, 1H), 2.72 (br s, 1H), 4.19 (m, 1H),
4.23 (q, 3H); 13C{1H}NMR (CDCl3) δ 14.2, 21.5, 23.2, 24.4, 43.5,
61.6, 69.0, 175.9; HRMS (EI, direct insert) m/z 160.1105 (M+, exact
mass calcd for C8H16O3, 160.1099); ee determination (GC, Macherey
Nagel FS-Lipodex A, 85 °C, isothermal) (S) t1 ) 9.05 min, (R) t2 )
9.42 min.
1
3
[R]25 ) +6.0° (c 0.50, CHCl3); H NMR (CDCl3) δ 0.89 (t, JHH
)
D
6.7 Hz, 3H), 1.28 (t, 3JHH ) 7.1 Hz, 3H), 1.36 (m, 6H), 1.49 (m, 2H),
1.49 (m, 2H), 1.96 (m, 2H), 4.23 (q, 3JHH ) 7.1 Hz, 2H), 5.20 (t, 3JHH
) 6.3 Hz, 1H), 7.46, 8.08, 8.10 (m, 5H); 13C{1H} NMR (CDCl3) δ
13.6, 13.7, 22.1, 24.8, 28.5, 30.8, 31.2, 60.7, 72, 128.0, 129.2, 129.3,
132.8, 165.5, 169.7; HRMS (EI, direct insert) m/z 292.1675 (M+, exact
mass calcd for C17H24O4, 292.1669); ee determination (HPLC, Daicel
Chiracel-OJ, 2% 2-PrOH-hexanes, 0.6 mL/min) (S) t1 ) 15.5 min,
(R) t2 ) 16.2 min.
(S)-2-Hydroxy-3-phenylpropanoic acid, Methyl Ester:21 [R]25
)
D
1
-21.1° (c 0.12, C6H6); H NMR (CDCl3) δ 1.28 (t, JHH ) 7.2 Hz,
3H), 2.74 (br, 1H), 3.02 (m, 2H), 4.22 (q, JHH ) 7.2 Hz, 2H), 4.38 (m,
1H), 7.20-7.35 (m, 5H); 13C{1H} NMR (CDCl3): δ14.0, 40.8, 61.9,
70.6, 126.8, 128.9, 129.0, 136.4, 173.5; ee determination (HPLC
Chiralcel OD-H column, 99:1 hexane-i-PrOH) (S) t1 ) 29.7 min, (R)
t2 ) 31.5 min, >98% ee.
(S)-2-(Benzoyloxy)-3-cyclohexylpropanoic Acid, Methyl Ester
[(S)-5h-OBz]: oil; [R]20D ) -13.5° (c 0.33, CHCl3); 1H NMR (CDCl3)
Synthesis of 1,2-Diols 11: Typical Procedure. A sample of
2-acyloxy ester 5 (typically ca. 50 mg) was dissolved in 5 mL of diethyl
ether cooled to 0 °C, and a 10-fold excess of LiAlH4 was added. The
mixture was allowed to warm to room temperature, and then stirred
for 12 h. The resulting suspension was cooled to 0 °C and quenched
with excess ethyl acetate, after which 5 mL of saturated NH4Cl was
added. The mixture was then evaporated to dryness, the resulting
residue extracted into ethyl acetate (ca. 10 mL) and washed with brine
and the aqueous washings re-extracted with additional portions of ethyl
acetate. The organic fractions were collected, dried over MgSO4, and
finally evaporated to afford the corresponding 1,2-diols 11 in good yield.
3
3
δ 0.90-1.95 (m, 11H), 1.26 (t, JHH ) 5.4 Hz, 3H), 4.21 (q, JHH
)
3
5.4 Hz, 2H), 5.27 (dd, JHH ) 7.2, 3.0 Hz, 1H), 7.40-8.10 (m, 5H);
13C{1H} NMR (CDCl3) δ 14.1, 26.0, 26.2, 26.3, 32.3, 33.7, 34.1, 38.5,
61.2, 71.2, 128.4, 129.6, 129.8, 133.2, 166.1, 170.8; HRMS (FAB) m/z
291.1588 (MH+ exact mass calculated for C17H23O4, 291.1596); ee
determination (HPLC, Daicel Chiracel-OJ, 2% 2-PrOH-hexanes, 0.6
mL/min) (S) t1 ) 15.5 min, (R) t2 ) 16.2 min.
(S)-2-Acetoxy-3-phenylpropanoic Acid, Ethyl Ester [(S)-5i-
1
OAc]: oil; [R]20 ) -8.8° (c 0.41, CHCl3); H NMR (CDCl3) δ 1.22
D
(t, 3H, 3JHH ) 5.4 Hz), 2.08 (s, 3H), 3.13 (m, 2H), 4.17 (q, 3JHH ) 5.4
Hz, 2H), 5.20 (dd, J
) 6.6, 3.6 Hz, 1H), 7.20-7.60 (m, 5H); 13C
HH
(R)-4-Methyl-1,2-pentanediol:22 [R]25D ) +31.8° (c 0.96, EtOH);
NMR (CDCl3) δ 14.0, 20.6, 37.3, 61.4, 73.0, 127.0, 128.5, 129.1, 130.0,
162.0, 169.6; HRMS (EI, direct insert) m/z 235.0965 (M - H+, exact
mass calculated for C13H15O4, 235.0970); ee determination (HPLC,
Daicel Chiracel-OD, 3% 2-PrOH-hexanes, 0.5 mL/min) (R) t1 ) 13.1
min, (S) t2 ) 14.5 min.
3
3
1H NMR (CDCl3) δ 0.92 (d, JHH ) 6.6 Hz, 3H), 0.97 (d, JHH ) 6.6
Hz, 3H), 1.20 (m, 1H), 1.40 (m, 1H), 1.75 (m, 1H), 2.25 (br s, 2H),
3.42 (m, 1H), 3.64 (m, 1H), 3.80 (m, 1H); 13C{1H} NMR (CDCl3) δ
22.0, 23.3, 24.4, 42.0, 67.1, 70.4; ee determination (GC, Chrompack
Chirasil-L-Val, 70 °C, isothermal) (R) t1 ) 18.87 min, (S) t2 ) 19.58
min.
(S)-2-(Benzoyloxy)-3-phenylpropanoic Acid, Methyl Ester [(S)-
1
5i-OBz]: oil; [R]20 ) -40.2° (c 1.85, MeOH); H NMR (CDCl3) δ
D
(S)-5-Methyl-1,2-hexanediol: oil; [R]25D ) -10.6° (c 0.70, EtOH);
3
3
3.25 (m, 2H), 3.70 (s, 3H), 5.40 (dd, JHH ) 8.1 Hz, J
) 5.1 Hz,
HH
3
3
1H NMR (CDCl3) δ 0.89 (d, JHH ) 6.6 Hz, 3H), 0.90 (d, JHH ) 6.5
Hz, 3H), 1.38 (m, 2H), 1.46 (m, 2H), 1.55 (m, 1H), 1.2-1.6 (m, 5H),
1.6 (vbr s, 2H), 3.45, 3.67 (m, 1H), 3.70 (m, 1H); 13C{1H} NMR
(CDCl3): δ 22.4, 22.5, 28.1, 31.0, 34.6, 66.8, 72.6; ee determination
(GC, Chrompack Chirasil-L-Val, 80 °C, isothermal) (R) t1 ) 23.41
min, (S) t2 ) 23.99 min.
1H), 7.20-8.05 (m, 10H); 13C{1H} NMR (CDCl3) δ 37.5, 52.3, 73.4,
127.0, 128.3, 128.5, 129.1, 129.3, 129.7, 133.3, 135.8, 165.8, 170.0;
HRMS (FAB) m/z 285.1119 (MH+ exact mass calculated for C17H17O4,
285.1127); ee determination (HPLC, Daicel Chiracel-OJ, 15% 2-PrOH-
hexanes, 0.5 mL/min) (R) t1 ) 29.0 min, (S) t2 ) 39.9 min.
(S)-2-(Benzoyloxy)-3-(â-naphthyl)propionic Acid, Ethyl Ester
[(S)-5j-OBz]: oil; [R]25D ) -59.6° (c 0.46, CHCl3); 1H NMR (CDCl3)
(20) Mori, K.; Akao, K. Tetrahedron 1979, 36, 91.
(21) Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J.
Org. Chem. 1986, 51, 2402.
(22) Hasegawa, J.; Ogura, M.; Tsuda, S.; Maemoto, S.; Kutsuki, H.;
Ohashi, T. J. Agric. Biol. Chem. 1990, 54, 1819.
3
3
δ 1.26 (t, JHH ) 6.9 Hz, 3H), 3.46 (m, 2H), 4.20 (q, JHH ) 7.1 Hz,
2H), 5.52 (dd, 3JHH ) 7.6, 5.3 Hz, 1H), 7.39, 7.44, 7.58, 7.78, 8.02 (m,
aromatics); 13C{1H} NMR (CDCl3) δ 14.3, 38.0, 61.7, 74.2, 126.4-
126.9, 128.2-130.2, 133.3-134.6 (aromatics); HRMS (EI, direct insert)

EnantioselectiVe Hydrogenation of Enol Esters
J. Am. Chem. Soc., Vol. 120, No. 18, 1998 4353
(S)-1,2-octanediol:22 [R]25 ) -15.4° (c 0.33, EtOH); 1H NMR
Acknowledgment. M.J.B. gratefully acknowledges the
National Institutes of Health (Grant GM 51342), Union Carbide
(Innovative Recognition Award), Eli Lilly (Grantee Award),
National Science Foundation (Grant CHE-9520305), and Duke
University for financial support. We thank Dr. G. R. Dubay
for obtaining HRMS data. A.P. gratefully acknowledges a
postdoctoral fellowship from the Spanish Ministery of Educa-
tion.
D
(CDCl3) δ 0.85 (m, 3H), 1.30 (br s, 6H), 1.40 (br s, 2H), 2.25 (br s,
2H), 3.45 (m, 1H), 3.70 (m, 2H); 13C{1H} NMR (CDCl3) δ 14.0, 22.6,
25.5, 29.3, 31.7, 33.0, 66.7, 72.3; HRMS (EI, direct insert) m/z 145.1223
(M - H+, exact mass calcd for C8H17O2, 145.1229); ee determination
(GC, Chrompack Chirasil-L-Val, 90 °C, 2 deg/min) (R) t1 ) 20.18
min, (S) t2 ) 20.96 min.
(S)-3-(â-Naphthyl)-1,2-propanediol:23 [R]25 ) -32.7°(c 0.55,
D
1
EtOH); H NMR (CDCl3) δ 2.42 (br s, 2H), 2.93 (m, 2H), 3.60 (m,
2H), 4.03 (m, 1H); 13C{1H} δ 39.9, 66.0, 72.9, 125.5, 126.1, 127.5,
127.6, 127.8, 128.3, 132.2, 133.5, 135.2; HRMS (EI, direct insert) m/z
202.0990 (M+, exact mass calcd for C13H14O2, 202.0994); HPLC Daicel
Chiracel-OJ, 25% 2-PrOH/Hexanes, 0.5 mL/min) (R) t1 ) 26.9 min,
(S) t2 ) 29.3 min.
Supporting Information Available: Representative chro-
matograms showing enantiomeric excess determinations for 5,
10, and 11 (3 pages, print/PDF). See any current masthead page
for ordering information and Web access instructions.
(23) Becker, H.; King, B. S.; Taniguchi, M.; Vanhessche, P. M. K.;
Sharpless, K. B. J. Org. Chem. 1995, 60, 3940.
JA974278B